WARNINGS

Cardiovascular Effects

Cardiovascular Thrombotic Events

Clinical trials of several COX-2 selective and nonselective NSAIDS of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal. All NSAIDs, both COX-2 selective and nonselective, may have a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with an NSAID, the lowest effective dose should be used for the shortest duration possible. Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms. Patients should be informed about the signs and/or symptoms of serious CV events and the steps to take if they occur.

There is no consistent evidence that concurrent use of aspirin mitigates the
increased risk of serious CV thrombotic events associated with NSAID use. The
concurrent use of aspirin and an NSAID does increase the risk of serious GI
events (see WARNINGS: Gastrointestinal (GI) Effects-Risk of Ulceration, Bleeding,
and Perforation).

Two large, controlled, clinical trials of a COX-2 selective NSAID for the treatment
of pain in the first 10 to 14 days following CABG surgery found an increased incidence of myocardial infarction and stroke (see CONTRAINDICATIONS).

Hypertension

NSAIDs, including TOLECTIN (tolmetin sodium) , can lead to onset of new hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs. NSAIDs, including TOLECTIN (tolmetin sodium) , should be used with caution in patients with hypertension. Blood pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout the course of therapy.

Congestive Heart Failure and Edema

Fluid retention and edema have been observed in some patients taking NSAIDs.
TOLECTIN (tolmetin sodium) should be used with caution in patients with fluid retention or heart
failure.

NSAIDs, including TOLECTIN (tolmetin sodium) , can cause serious gastrointestinal adverse events
including inflammation, bleeding, ulceration, and perforation of the stomach,
small intestine or large intestine, which can be fatal. These serious adverse
events can occur at any time, with or without warning symptoms in patients treated
with NSAIDs. Only one in five patients who develop a serious upper GI adverse
event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation
caused by NSAIDS occur in approximately 1% of patients treated for 3 to 6 months,
and in about 2 to 4% of patients treated for one year. These trends continue
with longer duration of use, increasing the likelihood of developing a serious
GI event at some time during the course of therapy. However, even short-term
therapy is not without risk.

NSAIDs should be prescribed with extreme caution in those with a prior history
of ulcer disease or gastrointestinal bleeding. Patients with a prior history
of peptic ulcer disease and/or gastrointestinal bleeding who use NSAIDs have
a greater than 10- fold increased risk for developing a GI bleed compared to
patients with neither of these risk factors. Other factors that increase the
risk for GI bleeding in patients treated with NSAIDs include concomitant use
of oral corticosteroids or anticoagulants, longer duration of NSAID therapy,
smoking, use of alcohol, older age, and poor general health status. Most spontaneous
reports of fatal GI events are in elderly or debilitated patients and, therefore,
special care should be taken in treating this population.

To minimize the potential risk for an adverse GI event in patients treated with an NSAID, the lowest effective dose should be used for the shortest possible duration. Patients and physicians should remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. This should include discontinuation of the NSAID until a serious GI adverse event is ruled out. For high- risk patients, alternate therapies that do not involve NSAIDs should be considered.

Renal Effects

Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Acuteinterstitialnephritis with hematuria, proteinuria, and occasionally nephritic syndrome have been reported in patients treated with TOLECTIN (tolmetin sodium) . Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liverdysfunction, those taking diuretics and ACE inhibitors, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.

Advanced Renal Disease

No information is available from controlled clinical trials regarding the use of TOLECTIN (tolmetin sodium) in patients with advanced renal disease. Therefore, treatment with TOLECTIN (tolmetin sodium) is not recommended in these patients with advanced renal disease. If TOLECTIN (tolmetin sodium) therapy must be initiated, close monitoring of the patient's renal function is advisable.

Anaphylactoid Reactions

As with other NSAIDs, anaphylactoid reactions may occur in patients with known
prior exposure to TOLECTIN (tolmetin sodium) . TOLECTIN (tolmetin sodium) should not be given to patients with the
aspirin triad. This symptom complex typically occurs in asthmatic patients who
experience rhinitis with or without nasal polyps, or who exhibit severe, potentially
fatal bronchospasm after taking aspirin or other NSAIDS (see CONTRAINDICATIONS
and PRECAUTIONS: Preexisting Asthma). Emergency help should be sought
in cases where an anaphylactoid reaction occurs.

Skin Reactions

NSAIDs, including TOLECTIN (tolmetin sodium) , can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Patients should be informed about the signs and symptoms of serious skin manifestations and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity.

Pregnancy

In late pregnancy, as with other NSAIDs, TOLECTIN (tolmetin sodium) should be avoided because
it may cause premature closure of the ductus arteriosus (see also PRECAUTIONS:
Pregnancy).

PRECAUTIONS

General

TOLECTIN (tolmetin sodium) cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids.

The pharmacological activity of TOLECTIN (tolmetin sodium) in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions.

Ophthalmological Effects

Because of ocular changes observed in animals and of reports of adverse eye findings with NSAIDs, it is recommended that patients who develop visual disturbances during treatment with TOLECTIN (tolmetin sodium) have ophthalmologic evaluations.

Hepatic Effects

Borderline elevations of one or more liver tests may occur in up to 15% of
patients taking NSAIDs, including TOLECTIN (tolmetin sodium) . These laboratory abnormalities may
progress, may remain unchanged, or may be transient with continuing therapy.
Notable elevations of ALT or AST (approximately three or more times the upper
limit of normal) have been reported in approximately 1% of patients in clinical
trials with NSAIDs. In addition, rare cases of severe hepatic reactions, including
jaundice and fatal fulminant hepatitis, liver necrosis, and hepatic failure,
some of them with fatal outcomes have been reported.

A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred should be evaluated for evidence of the development of a more severe hepatic reaction while on therapy with TOLECTIN (tolmetin sodium) . If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), TOLECTIN (tolmetin sodium) should be discontinued.

Hematological Effects

Anemia is sometimes seen in patients receiving NSAIDs, including TOLECTIN (tolmetin sodium) . This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including TOLECTIN (tolmetin sodium) , should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia. NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible. Patients receiving TOLECTIN (tolmetin sodium) who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored.

Preexisting Asthma

Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm which can be fatal. Since cross reactivity, including bronchospasm, between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, TOLECTIN (tolmetin sodium) should no t be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma.

Information for Patients

Patients should be informed of the following information before initiating
therapy with an NSAID and periodically during the course of ongoing therapy.
Patients should also be encouraged to read the NSAID Medication Guide that accompanies
each prescription dispensed.

TOLECTIN (tolmetin sodium) , like other NSAIDs, may cause serious CV side effects, such as
MI or stroke, which may result in hospitalization and even death. Although
serious CV events can occur without warning symptoms, patients should be alert
for the signs and symptoms of chest pain, shortness of breath, weakness, slurring
of speech, and should ask for medical advice when observing any indicative
signs or symptoms. Patients should be apprised of the importance of this follow-up
(see WARNINGS: Cardiovascular Effects).

TOLECTIN (tolmetin sodium) , like other NSAIDs, can cause GI discomfort and, rarely, serious
GI side effects, such as ulcers and bleeding, which may result in hospitalization
and even death. Although serious GI tract ulcerations and bleeding can occur
without warning symptoms, patients should be alert for the signs and symptoms
of ulcerations and bleeding, and should ask for medical advice when observing
any indicative signs or symptoms including epigastric pain, dyspepsia, melena,
and hematemesis Patients should be apprised of the importance of this follow-up
(see WARNINGS: Gastrointestinal (GI) Effects-Risk of Ulceration, Bleeding,
and Perforation).

TOLECTIN (tolmetin sodium) , like other NSAIDs, can cause serious skin side effects such as
exfoliative dermatitis, SJS, and TEN, which may result in hospitalizations
and even death. Although serious skin reactions may occur without warning,
patients should be alert for the signs and symptoms of skin rash and blisters,
fever, or other signs of hypersensitivity, such as itching, and should ask
for medical advise when observing any indicative signs or symptoms. Patients
should be advised to stop the drug immediately if they develop any type of
rash and contact their physicians as soon as possible.

Patients should promptly report signs or symptoms of unexplained weight
gain or edema to their physicians.

Patients should be informed of the warning signs and symptoms of hepatotoxicity
(e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant
tenderness, and "flu- like" symptoms). If these occur, patients should be
instructed to stop therapy and seek immediate medical therapy.

Patients should be informed of the signs of an anaphylactoid reaction (e.g.,
difficulty breathing, swelling of the face or throat). If these occur, patients
should be instructed to seek immediate emergency help (see WARNINGS).

In late pregnancy, as with other NSAIDs, TOLECTIN (tolmetin sodium) should be avoided because
it will cause premature closure of the ductus arteriosus.

Laboratory Tests

Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding. Patients on long-term treatment with NSAIDs should have their CBC and a chemistry profile checked periodically. If clinical signs and symptoms consistent with liver or renal disease develop, systemic manifestations occur (e.g., eosinophilia, rash, etc.) or if abnormal liver tests persist or worsen, TOLECTIN (tolmetin sodium) should be discontinued.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Tolmetin sodium did not possess any carcinogenic liability in the following long-term studies: a 24-month study in rats at doses as high as 75 mg/kg/day, and an 18- month study in mice at doses as high as 50 mg/kg/day.

No mutagenic potential of tolmetin sodium was found in the Ames Salmonella-Microsomal Activation Test.

Reproductive studies revealed no impairment of fertility in animals. Effects
on parturition have been shown, however, as with other prostaglandin inhibitors.
This information is detailed in the Pregnancy section.

Pregnancy

Teratogenic Effects: Pregnancy Category C

Reproduction studies in rats and rabbits at doses up to 50 mg/kg (1.5 times the maximum clinical dose based on a body weight of 60 kg) revealed no evidence of teratogenesis or impaired fertility due to TOLECTIN (tolmetin sodium) . However, animal reproduction studies are not always predictive of human response. There are no adequate and well- controlled studies in pregnant women. TOLECTIN (tolmetin sodium) should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nonteratogenic Effects

Because of the known effects of NSAIDs on the fetal cardiovascular system (closure
of ductus arteriosus), use during pregnancy (particularly late pregnancy) should
be avoided.

Labor and Delivery

In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia, delayed parturition, and decreased pup survival occurred. The effects of TOLECTIN (tolmetin sodium) on labor and delivery in pregnant women are unknown.

Nursing Mothers

Tolmetin sodium has been shown to be secreted in human milk. Because of the potential for serious adverse reactions in nursing infants from tolmetin sodium, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness in pediatric patients below the age of 2 years have
not been established.

Geriatric Use

As with any NSAIDs, caution should be exercised in treating the elderly (65
years and older).

Last reviewed on RxList: 2/11/2008
This monograph has been modified to include the generic and brand name in many instances.